Method of preparing z-aminopyrimi



Patented Aug. 26, 1941 Elmore Hathaway Nada, Bound Brook, N. J., assignor to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application March 25, 1941, Serial No. 385,137

15 Claims.

This invention relates to an improved process for reducing 2-amino-4-chloropyrimidlne to produce Z-aminopyrimldine.

Z-aminopyrimidine is used as an intermediate in the production of sulfanilamidopyrimidine which is of outstanding therapeutic importance. The production of the intermediate has, however, been very difficult in the past, involving a multistep process in which a crude 2-amino-4-chloropyrimidine is obtained by a halogenation of 2- amino-4-hydroxypyrimidine by means of phosphorus oxychloride or similar halogenating agents. This crude product cannot be satisfactorily reduced with hydrogen catalytically as it contains impurities which poisonthe catalyst. Purification to a degree which permits catalytic reduction is economically unsatisfactory on a commercial scale.

Attempts to reduce the compound in neutral or acid solution with zinc dust have also been, for the most part, unsuccessful. In orderto proceed at all, very dilute solutions have to be used and even in such a case the yields are poor.

An improved process is described in the copending application of Kuh and Hultquist, Patent No. 2,242,079, patented May 13, 1941, in which the reduction is carried out under alkaline conditions and preferably using sodium. or potassium phosphates as the alkali. This procedure, for the first time, made the reduction step practicable for of the reduction.

The amount-of the ammonium radical present in therea etion mixture is not critical and various amounts may be used. -In general, however, it is desirable to use about one-tenth as much ammonium ions as alkali metal ions in the reaction. When the amount of ammonium ions is reduced much below this proportion the elimination of foaming and acceleration of the reduction slowly decreases. Amounts of ammonium compounds in excess of the 10% do not give materially improved results which would justify the additional cost and therefore the approximate ratio of 1 part of ammonium to 10 parts of sodium' or other alkali metal, is a preferred modification based on the economics of the process. The alkali metal is preferably supplied in the form of a salt with a weak acid such as the carbonate, bicarbonate, phosphate or hydrogen phosphate.

The" ammonium may be added as ammonium hydroxide, ammonium phosphate or other salt and I have found that when added as the phosphate or the hydroxide it appears to act with maximum efiiciency although the invention is not broadly limited to the addition of the ammonium radical in these forms.

The method of addition of the ammonium compound can be varied. For example, a crude 2- amino-4-chloropyrimidine mixture may be neutralized with ammonia, filtered oil, and the mother liquor used as a source of ammonium ions. This has the advantage that the crude 2- amino-l-chloropyrimidine may be used as a wet cake without washing or other purification. The effect of the ammonium compound is just the same but the method presents certain operating advantages and is therefore preferred.

The invention will be described in'detail in conjunction with the following specific examples which represent typical applications of the invention. The parts are by weight.

Example 1 500 parts of water are heated to C. and to it is added 45, parts of anhydrous trisodium phosphate and 50 parts of zinc dust followed by 4.5 parts of ammonium phosphate. The mixture is heated to boiling and the wet cake of 2-amino-4- chloropyrimidine, resulting from 66 parts of isocytosine is added over about 30 minutes, simultaneously with an additional parts of zinc dust. The reaction is then boiled for about hour. After the reduction is complete, the mixture is cooled to 25 C. and the zinc dust residue filtered and washed with as little water as possihie. The filtrate is cooled below 10 C. and is treated with 127.5 parts of flake sodium hydroxide, the temperature being kept below 25 C. by external cooling. The Z-aminopyrimidine which is insoluble in this concentration of alkali is precipitated and is then filtered. The filter cake and the filtrate are both extracted with hot toluene which is then evaporated to give a product in the form of light colored needles. The yield is 55.5% of theory based on isocytosine.

Example 2 Water is heated to 80 C. and 63 parts of trisodlum phosphate, 50 parts of zinc dust and parts of aqua ammonia by volume are added. This mixture is heated to a boil and with constant stirring 505 parts of wet cake or 2-amino-4- chloropyrimidine, containing about 65 parts of actual chloro-compound, is added over hour simultaneously with 150 parts of zinc dust. After /2 hour heating, reduction is-complete. The mixture is heated for another /2 hour, then cooled to 25 C., filtered and the zinc residue is washed with as little water as possible.

The filtrate is cooled to C. and 250 parts or sodium hydroxide are added, the temperature being kept below 20 C. The Z-aminopyrimidine precipitates as a thick slurry and isfiltered. The wet filter cake is dissolved in mixed amyl alcohols and the small aqueous layer returned to the main mother liquor, which is then extracted three times with the volume or mixed amyl alcohols. The combined amyl alcohol solutions are treated with 36% hydrochloric acid to pH of 3.5 and the layer of 2-aminopyrimidine hydrochloride which separates is neutralized to a pH of 8 with 50% sodium hydroxide. 2'-aminopyrimidine is filtered from the cold slurry and dried. The mother liquor is re-extracted with amyl alcohol resulting in a small recovery. Yield, based on isocytosine, is 68% of theory.

Example 3 467 parts of water are heated to 60 C. and 42.0 parts of anhydrous trisodium phosphate along with 4.6 parts of ammonium phosphate and 1.5 parts of ammonium hydroxide are added. When the temperature reaches 90 C., fifty parts of zinc dust, and at 100 0., 100 parts of zinc dust are added. At the boiling point of the contents of the flask, 46.7 parts of 2-amino-4- chloropyrimidine are added with vigorous stirring as fast as it disappears from the surface of the liquid. After one-fourth of the 2-amino-4-chloropyrimidine has been added, 37 parts of zinc dust are added. After all the 2-amino-4- chloropyrimidine has been added the contents of the flask are held at the boiling pointfor one to one and one-half hours. If the reduction is complete the liquid is cooled; the zinc is filtered off, and the Z-aminopyrimidlne is precipitated by adding caustic soda to form a -18% solution. Yield of pure 2-aminopyrimidine i 87.5% based on 2-amino-4-chloropyrimidine.

Eaample 4 Water was heated to 80 C. and 63 parts of trisodium phosphate, 50 parts of zinc dust and 5 parts by volume of aqua ammonia were added. This mixture was heated to a boil and with constant stirring 505 parts of wet cake oi. 2-amino- 4-chloropyrimidine, containing about 65 parts oi! actual chloro-compound, was added over 10 minutes simultaneously with 150 parts of zinc dust. After one-half hour heating test showed complete reduction. The mixture was heated for another one-half hour. then cooled to 25 C., filtered, and the zinc dust washed with as little water as possible.

The filtrate was cooled to 10 C. and 250 parts of caustic soda were added, the temperature being kept below C. The 2-aminopyrimidine precipitated in a thick slurry and was filtered. The strong caustic filtrate was shaken with 400 parts of benzene to extract any dissolved base.

The filter cake was extracted with benzene at the boiling point of the benzene. Upon cooling, the pure white 2-aminopyrimidlne crystallized out and was filtered. Yield was 38.5 parts corresponding to 68% of theory based on the isocytosine used for preparing the crude 2-amino-4- chloropyrimidin'e.

Example 5 A mixture of 5 parts 2-amino-4-chloropyrimidine, 15 parts of zinc dust, 40 parts of water and 6 parts of ammonium carbonate were mixed and heated to 90-95 C. Considerable foaming took place at 'l090 C. The chloro compound had all dissolved after five minutes of heating,

and reduction was complete in minutes more. The mixture was cooled to C., the zinc sludge was filtered oil and the colorless filtrate was treated with 5 parts of sodium hydroxide and extracted with four 100 part portions of ether. Evaporation of the ether gave 3.1 parts of colorless 2-aminopyrimidine corresponding to 85% of theory.

Example 6' A mixture of 350 parts of water and 50 parts of sodium bicarbonate was heated to 60 C. under agitation, 165 parts of zinc dust and 5 parts of 28% ammonia was added, and this mixture was heated to 85-95 C. To this was added over 20 minutes, 180 parts wet cake containing 55 parts of crude 2-amino-4-chloropyrimidine and 125 parts of water, keeping the temperature at 90-95 C. After all the materials were added, the mixture was held at 95-100 C. for 30 minutes, cooled to 30 C. and the zinc sludge was filtered off. The nearly colorless :filtrate amounted to 550 parts. A 100 part portion was treated with 12 parts oi sodium hydroxide and was then extracted with four 100 part portions or isopropyl acetate. Evaporation of this isopropyl acetate extract gave 6.1 parts of almost colorless 2- aminopyrimidine. This corresponds to a yield of 33.6 parts or 83% of theory.

Example 7 A mixture of 2000 parts of water, 260 parts of 2-amino-4-chloropyrimidine, 180 parts of 28% ammonia water, and 780 parts of zinc dust were mixed in an autoclave. After closing the autoclave the mixture was heated to C. and held at this temperature for 1% hours. During this time the pressure rose to 75 lbs. per sq. in. The charge was cooled to 45" C., the pressure released, and the zinc dust filtered ed. A part portion of the 2480 parts or filtrate was treated with 12 parts of caustic and the 2-aminopyrimidine was extracted with isopropyl acetate. Evaporation of the isopropyl acetate gave 5.9 parts or almost; colorless Z-aminopyrimidine, equivalent to a total yield from the whole run of 146.3 parts or 76% of the theory.

What I claim is:

1. A method of reducing 2-amino-4-chloropyrimidine to Z-aminopyrlmidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc under alkaline conditions in the presence of an effective amount 01' the ammonium ion.

2. A method of reducing crude 2-amino-4- chloropyrimidine obtained from the halogenation of 2-amino-4-hydroxypyrimidine with phosphorus halogen compounds to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc under alkaline conditions in the presence of an efiective amount 01' an ammonium ion.

3. A method of reducing 2-amino-4-chloropyrimidine to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of sufiicient alkali metal phosphates to produce alkaline conditions and in the presence 01 an eflective amount of an ammonium ion.

4. A method of reducing 2-amino-4-chloropyrimidine to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of sufficient alkali metal phosphates to produce alkaline conditions and in the presence of an effective amount of ammonium phosphate.

5. A method of reducing crude 2-amino-4- chlonopyrimidine obtained from the halogenation or z-amino-i-hydroxypyrimidine with phosphorus halogen compounds to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of sufilcient alkali metal phosphates to produce alkaline conditions and in the presence of an efl'ective amount of ammoniumion.

6. A method of reducing crude 2-amino-4- chloropyrimidine obtained from the halogenation of 2-amino-4-hydroxypyrimidine with phosphorus halogen compounds to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of suilicient alkali metal phosphates to produce alkaline conditions and in the presence of an eflective amount of ammonium phosphate.

7. A method according to claim 3 in which the amount of the ammonium ion is approximatelyone-tenth that of the alkali metal ion in the phosphates.

8. A method according'to claim 4 in which the amount or the ammonium phosphate is approximately one-tenth that of the alkali metal phosphates.

9. A method oi obtaining z-aminopyrimidine from crude 2-amino-4-chloropyrimidlne obtained by the halozenation oi 2-amino-4-hydroxypyrimidine which comprises neutralizing the acidity of the crude 2-amino-4-chloropyrimidine with ammonia. subjecting the neutralized 2-amino-4-chloropyrimidine in aqueous dispersion to the action of finely divided metallic zinc in alkaline solution and adding a sumcient amount of the mother liquor from the neutralization to introduce an efiective amount of ammonium. ion into the reaction mixture.

10. A method of reducing 2-amino-4-chloropyrimidine to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of a sufiicient amount of an alkali metal carbonate to produce alkaline conditions and in the presence of an efl'ective amount of an ammonium ion.

11. A method of reducing crude 2-amino-4- chloropyrimidine obtained from the halogena tion of. 2-amino-4-hydroxypyrimidine with phosphorus halogen compounds to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of a sufllcient amount of an alkali metal carbonate to produce alkaline conditions and in the presence of an effective amount oi; an ammonium ion.

12. A method 01' reducing 2-amino-4-chloropyrimidine to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of a suflicient amount 01' sodium bicarbonate to produce alkaline conditions and in the presence of an eflective amount oi an ammonium ion.

13. A method of reducing crude 2-amino-4- chloropyrimidine obtained from the halogenation 0i 2-amino-4-hydr0myr1midine with phosphorus halogen compounds to 2-aminopyrimidine which comprises treating the material in aqueous dispersion with finely divided metallic zinc in the presence of a sumcient amount of sodium bicarbonate to produce alkaline conditions and in the presence of an eflective amount or an ammonium ion.

14. A method according to claim 12 in which the ammonium ion is in the form of ammonium hydroxide.

15. A method according to claim 13 in which the ammonium ion is in the form. of ammonium hydroxide.

muons: HATHAWAY NOR'I'HEY. 

